The present invention relates generally to methods for diagnosing and treating conditions associated with abnormal vasculature.
Fluorescent dyes, such as indocyanine green (ICG), have been used for years in connection with angiography to diagnose and treat vascular abnormalities that occur in the eye, e.g., choroidal neovascularization (CNV). CNV is a cause of Age-Related Macular Degeneration (ARMD), which is the leading cause of significant visual impairment in the elderly.
CNV originates in the choroidal blood vessels, the latter lying adjacent the retina of the eye. When CNV forms, it may intrude into and displace a portion of the sensory retina from its normal position, thereby distorting vision. Vision may also be blocked entirely if hemorrhage of the CNV occurs.
One method of diagnosing and treating ARMD is by laser photocoagulation of the CNV. This treatment, however, is successful to the extent that the CNV can be accurately mapped. This is because the CNV is, by definition, in the macular area and often encroaches on the fovea. Application of photocoagulation close to the fovea can result in the destruction of high acuity vision and/or accelerated growth of the CNV.
Generally, mapping of CNV is completed using angiograms. Angiograms are images of blood vessels, obtained by injecting a fluorescent dye into the blood stream prior to obtaining an image. As any of several dyes may be used, and because each dye fluoresces at its own particular wavelength, a radiation source that emits light (radiation) at that particular wavelength (e.g., a low-powered laser provided using fiber optic cables incorporated into a fundus camera) is used to illuminate the eye. Such a light source is part of a fundus camera, which also includes a CCD video camera. At or about the time of dye injection into the animal, the fundus camera begins capturing images, i.e., angiograms, of the eye at specific time intervals. The angiograms provide a record of the extent of dye movement within the ocular vasculature at each specific time interval.
More specifically, after the dye is injected into the body, the dye enters the vasculature of the eye and begins to fluoresce due to the presence of the appropriate excitation radiation (light). The fluorescing dye, being mixed with the ocular blood, provides each angiogram with an accurate illustration of the extent of ocular blood flow through the ocular vasculature at that moment. By comparing a series of angiograms of the same vasculature over a given time period, one is able to map the vasculature and determine the location of a CNV, and may then move to treat this abnormality, e.g., by laser photocoagulation of the CNV itself.
While the foregoing methodology has met with success, several issues remain. One is the clarity of the angiograms obtained using the previously described diagnostic methods. Clearly, any improvements in the angiogram clarity would result in a more accurate diagnosis, and, more significantly, allow a physician to more accurately locate a CNV requiring treatment.
Further, the medical uses of fluorescent dyes outside of the foregoing diagnosis and treatment procedures has been relatively limited. Other known uses for one such dye, ICG, are limited to diagnostic procedures, such as determining cardiac output, hepatic function and liver blood flow.
Accordingly, a need exists for methods of diagnosing and treating ocular vascular abnormalities, e.g., CNV, that overcome the aforementioned problems inherent in known methods of fluorescent dye angiography and photocoagulation. Further, and in view of the successful use of fluorescent dyes as diagnostics for certain limited conditions, i.e., ophthalmic angiograms, hepatic function and liver blood flow and cardiac output, there remain questions as to whether the use of these dyes can successfully be expanded into the diagnosis and/or treatment of other conditions and disorders.
The present invention meets the foregoing and other needs in a variety of ways. In a first aspect, the present invention provides a method for enhancing the clarity of fluorescent dye angiograms using relatively high dye concentrations, leading to more accurate targeting of vessels during treatment. In a second aspect, the present invention provides a method that allows blood vessels feeding various types of abnormalities to be more readily identified, and thereafter treated. Several other aspects of the present invention provide new methods of diagnosis and treating abnormalities and conditions using fluorescent dyes. All of the inventive aspects may be used on animals, e.g., humans, dogs, cats, but are preferably used in connection with the diagnosis and treatment of human subjects.
In particular, the present invention is able to provide angiograms of enhanced clarity by administering a plurality of relatively small boluses at relatively high dye concentrations to an animal undergoing an angiographic procedure. In particular, the method includes introducing boluses of about 0.1 ml to about 1.0 ml of a liquid composition at spaced time intervals into the animal to at least partially fill the blood vessels with the composition, wherein the liquid composition comprises a relatively high fluorescent dye and a carrier. For example, when using ICG, the dye concentration would be at least about 30 mg/ml, preferably at least about 40 mg/ml and most preferably at least about 50 mg/ml. Light energy of a type and in an amount sufficient to cause the dye in each bolus to fluoresce as the dye flows through the blood vessels is then applied, and angiographic images obtained.
Another aspect of the present invention provides a method for determining the direction of blood flow within a vessel. This may allow a physician to more readily determine whether a particular vessel is feeding an abnormality, indicating that it should be treated. The method includes at least the steps of administering a liquid composition comprising a fluorescent dye and a carrier into the animal to at least partially fill the blood vessel with the composition. Energy of a type and in an amount sufficient to cause the dye in the blood vessel to fluoresce is then applied. Subsequently, energy of a type and in an amount in excess of that required to cause the dye to fluoresce is applied to a portion of the fluorescing dye passing through the blood vessel to cause that portion of the fluorescing dye to stop fluorescing. A series of angiographs of both the fluorescing dye, and of the subsequent non-fluorescing portion thereof (also referred to as the xe2x80x9cbleachedxe2x80x9d dye portion), are obtained, and those angiograms are compared to determine the direction of relative movement of the bleached dye. The direction of relative movement of the bleached dye portion indicates the direction of relative movement of the blood flow in the blood vessel.
Other aspects of the present invention involve new indications for fluorescent dyes. For example, one indication permits a physician to locate a tumor in or adjacent to the wall of a body cavity of an animal. This method includes administering a liquid composition comprising a fluorescent dye and a carrier into the animal to at least partially fill the blood vessels of the body cavity with the composition; applying energy of a type and in an amount sufficient to cause the dye to fluoresce as the dye flows through the blood vessels of the body c obtaining at least one angiographic image of the fluorescing dye as the dye flows through the blood vessels of the body cavity; and analyzing the angiographic image obtained in the prior step to determine whether a tumor is present in or adjacent to the wall of the body cavity. Related methods for diagnosing other types of lesions, e.g., ruptured blood vessels, abnormal vasculature, are also provided.
In other important aspects, the present invention provides methods for treating the aforementioned conditions. One exemplary method reduces the blood flow through a vessel that carries blood into a tumor of an animal. This method comprises administering a liquid composition comprising a fluorescent dye and a carrier into the animal to at least partially fill a blood vessel that carries blood into a tumor with the composition, and applying energy to the blood vessel of a type and in an amount sufficient to excite the dye in the blood vessel, thereby increasing the temperature of any liquid adjacent the dye, the increase in temperature causing the blood within the vessel to coagulate relatively quickly, thereby reducing (and preferably halting completely) the rate of blood flow through that vessel into the tumor.
Other related aspects of the present invention include methods for reducing or eliminating tumors. These methods are preferably used after the tumors have been located using fluorescent dye angiography, the latter providing a means for precisely locating a tumor in a subject. Once the precise location of a tumor is determined, methods including dye-enhanced photocoagulation, direct injection of chemotherapeutic and/or anti-angiogenesis agents into the tumor, conventional application of radiation, and surgical removal of the tumor, are expected to be effective against the tumor when used either alone or in combination. These methods have the advantage of lessening patient trauma because the treatment can be closely focused on the tumor alone as opposed to the tumor and other healthy body tissue, and may be used in combination in a single treatment session. For example, a single session can include dye-enhanced photocoagulation of those vessels feeding blood into the tumor using an endoscope, followed by injection of chemotherapeutic and anti-angiogenesis agents via the endoscope directly into the tumor itself (as opposed to conventional IV administration).
The various aspects of the present invention will be more clearly understood upon reference to the following preferred embodiments.